Dosage Regimen for the Treatment of Cancer

ABSTRACT

The present specification relates to AZD9833 for use in the treatment of cancer and methods of treatment of cancer involving administration of AZD9833 wherein, in each case, the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg. AZD9833 may be administered alone or its use may be in combination with an additional anti-cancer agent such as a CDK inhibitor, everolimus or an AKT inhibitor.

FIELD

The present specification relates toN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine(AZD9833, Compound (I) below) for use in the treatment of cancer,characterised in that the compound is for once daily oral administrationin a specified dose. The specification also relates to methods oftreatment involving once daily oral administration of AZD9833 in aspecified dose to a patient in need thereof, the use of AZD9833 for theproduction of a medicament where the medicament is for once daily oraladministration in a specified dose, pharmaceutical compositionscomprising certain amounts of AZD9833 and kits of such pharmaceuticalcompositions.

BACKGROUND

Estrogen receptor alpha (ERα, ESR1, NR3A) and estrogen receptor beta(ERβ, ESR2, NR3b) are steroid hormone receptors which are members of thelarge nuclear receptor family. Structured similarly to all nuclearreceptors, ERα is composed of six functional domains (named A-F)(Dahlman-Wright, et al., Pharmacol. Rev., 2006, 58:773-781) and isclassified as a ligand-dependent transcription factor because after itsassociation with the specific ligand, (the female sex steroid hormone17b estradiol (E2)), the complex binds to genomic sequences, namedEstrogen Receptor Elements (ERE) and interacts with co-regulators tomodulate the transcription of target genes. The ERα gene is located on6q25.1 and encodes a 595AA protein and multiple isoforms can be produceddue to alternative splicing and translational start sites. In additionto the DNA binding domain (Domain C) and the ligand binding domain(Domain E) the receptor contains a N-terminal (A/B) domain, a hinge (D)domain that links the C and E domains and a C-terminal extension (Fdomain). While the C and E domains of ERα and ERβ are quite conserved(96% and 55% amino acid identity respectively) conservation of the A/B,D and F domains is poor (below 30% amino acid identity). Both receptorsare involved in the regulation and development of the femalereproductive tract and in addition play roles in the central nervoussystem, cardiovascular system and in bone metabolism. The genomic actionof ERs occurs in the nucleus of the cell when the receptor binds EREsdirectly (direct activation or classical pathway) or indirectly(indirect activation or non-classical pathway). In the absence ofligand, ERs are associated with heat shock proteins, Hsp90 and Hsp70,and the associated chaperone machinery stabilizes the ligand bindingdomain (LBD) making it accessible to ligand. Liganded ER dissociatesfrom the heat shock proteins leading to a conformational change in thereceptor that allows dimerization, DNA binding, interaction withco-activators or co-repressors and modulation of target gene expression.In the non-classical pathway, AP-1 and Sp-1 are alternative regulatoryDNA sequences used by both isoforms of the receptor to modulate geneexpression. In this example, ER does not interact directly with DNA butthrough associations with other DNA bound transcription factors e.g.c-Jun or c-Fos (Kushner et al., Pure Applied Chemistry 2003,7a:1757-1769). The precise mechanism whereby ER affects genetranscription is poorly understood but appears to be mediated bynumerous nuclear factors that are recruited by the DNA bound receptor.The recruitment of co-regulators is primarily mediated by two proteinsurfaces, AF2 and AF which are located in the E-domain and the A/Bdomain respectively. AF1 is regulated by growth factors and its activitydepends on the cellular and promoter environment whereas AF2 is entirelydependent on ligand binding for activity. Although the two domains canact independently, maximal ER transcriptional activity is achievedthrough synergistic interactions via the two domains (Tzukerman, et al.,Mol. Endocrinology 1994, 8:21-30). Although ERs are consideredtranscription factors they can also act through non-genomic mechanismsas evidenced by rapid ER effects in tissues following E2 administrationin a timescale that is considered too fast for a genomic action. It isstill unclear if receptors responsible for the rapid actions of estrogenare the same nuclear ERs or distinct G-protein coupled steroid receptors(Warner, et al., Steroids 2006 1:91-95) but an increasing number of E2induced pathways have been identified e.g. MAPK/ERK pathway andactivation of endothelial nitric oxide synthase and PI3K/Akt pathway. Inaddition to ligand dependent pathways, ERα has been shown to have ligandindependent activity through AF-1 which has been associated withstimulation of MAPK through growth factor signalling e.g. insulin likegrowth factor 1 (IGF-1) and epidermal growth factor (EGF). Activity ofAF-1 is dependent on phosphorylation of Ser118 and an example ofcross-talk between ER and growth factor signalling is thephosphorylation of Ser 118 by MAPK in response to growth factors such asIGF-1 and EGF (Kato, et al., Science. 1995, 270:1491-1494).

A large number of structurally distinct compounds have been shown tobind to ER. Some compounds such as endogenous ligand E2, act as receptoragonists whereas others competitively inhibit E2 binding and act asreceptor antagonists. These compounds can be divided into 2 classesdepending on their functional effects. Selective estrogen receptormodulators (SERMs) such as tamoxifen have the ability to act as bothreceptor agonists and antagonists depending on the cellular and promotercontext as well as the ER isoform targeted. For example, tamoxifen actsas an antagonist in breast but acts as a partial agonist in bone, thecardiovascular system and uterus. All SERMs appear to act as AF2antagonists and derive their partial agonist characteristics throughAF1. A second group, fulvestrant being an example, are classified asfull antagonists and are capable of blocking estrogen activity via thecomplete inhibition of AF1 and AF2 domains through induction of a uniqueconformation change in the ligand binding domain (LBD) on compoundbinding which results in complete abrogation of the interaction betweenhelix 12 and the remainder of the LBD, blocking co-factor recruitment(Wakeling, et al., Cancer Res., 1991, 51:3867-3873; Pike, et al.,Structure, 2001, 9:145-153).

Intracellular levels of ERα are downregulated in the presence of E2through the ubiquitin/proteasome (Ub/26S) pathway. Polyubiquitinylationof liganded ERα is catalysed by at least three enzymes; theubiquitin-activating enzyme E1 activated ubiquitin is conjugated by E2with lysine residues through an isopeptide bond by E3 ubiquitin ligaseand polyubiquitinated ERα is then directed to the proteasome fordegradation. Although ER-dependent transcription regulation andproteasome-mediated degradation of ER are linked (Lonard, et al., Mol.Cell. 20005:939-948), transcription in itself is not required for ERαdegradation and assembly of the transcription initiation complex issufficient to target ERα for nuclear proteasomal degradation. This E2induced degradation process is believed to necessary for its ability torapidly activate transcription in response to requirements for cellproliferation, differentiation and metabolism (Stenoien, et al., Mol.Cell Biol., 2001, 21:4404-4412). Fulvestrant is also classified as aselective estrogen receptor down-regulator (SERD), a subset ofantagonists that can also induce rapid down-regulation of ERα via the265 proteasomal pathway. In contrast a SERM such as tamoxifen canincrease ERα levels although the effect on transcription is similar tothat seen for a SERD.

Approximately 70% of breast cancers express ER and/or progesteronereceptors implying the hormone dependence of these tumor cells forgrowth. Other cancers such as ovarian and endometrial are also thoughtto be dependent on ERα signalling for growth. Therapies for suchpatients can inhibit ER signalling either by antagonising ligand bindingto ER e.g. tamoxifen which is used to treat early and advanced ERpositive breast cancer in both pre- and post-menopausal setting;antagonising and down-regulating ERα e.g. fulvestrant which is used totreat breast cancer in women which have progressed despite therapy withtamoxifen or aromatase inhibitors; or blocking estrogen synthesis e.g.aromatase inhibitors which are used to treat early and advanced ERpositive breast cancer. Although these therapies have had an enormouslypositive impact on breast cancer treatment, a considerable number ofpatients whose tumors express ER display de novo resistance to existingER therapies or develop resistance to these therapies over time. Severaldistinct mechanisms have been described to explain resistance tofirst-time tamoxifen therapy which mainly involve the switch fromtamoxifen acting as an antagonist to an agonist, either through thelower affinity of certain co-factors binding to the tamoxifen-ERαcomplex being off-set by over-expression of these co-factors, or throughthe formation of secondary sites that facilitate the interaction of thetamoxifen-ERα complex with co-factors that normally do not bind to thecomplex. Resistance could therefore arise as a result of the outgrowthof cells expressing specific co-factors that drive the tamoxifen-ERαactivity. There is also the possibility that other growth factorsignalling pathways directly activate the ER receptor or co-activatorsto drive cell proliferation independently of ligand signalling.

More recently, mutations in ESR1 have been identified as a possibleresistance mechanism in metastatic ER-positive patient derived tumorsamples and patient-derived xenograft models (PDX) at frequenciesvarying from 17-25%. These mutations are predominantly, but notexclusively, in the ligand-binding domain leading to mutated functionalproteins; examples of the amino acid changes include Ser463Pro,Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn and Asp538Gly, with changesat amino acid 537 and 538 constituting the majority of the changescurrently described. These mutations have been undetected previously inthe genomes from primary breast samples characterised in the CancerGenome Atlas database. Of 390 primary breast cancer samples positive forER expression not a single mutation was detected in ESR1 (Cancer GenomeAtlas Network, 2012 Nature 490: 61-70). The ligand binding domainmutations are thought to have developed as a resistance response toaromatase inhibitor endocrine therapies as these mutant receptors showbasal transcriptional activity in the absence of estradiol. The crystalstructure of ER, mutated at amino acids 537 and 538, showed that bothmutants favoured the agonist conformation of ER by shifting the positionof helix 12 to allow co-activator recruitment and thereby mimickingagonist activated wild type ER. Published data has shown that endocrinetherapies such as tamoxifen and fulvestrant can still bind to ER mutantand inhibit transcriptional activation to some extent and thatfulvestrant is capable of degrading Try537Ser but that higher doses maybe needed for full receptor inhibition (Toy et al., Nat. Genetics 2013,45: 1439-1445; Robinson et al., Nat. Genetics 2013, 45: 144601451; Li,S. et al. Cell Rep. 4, 1116-1130 (2013). It is therefore feasible thatCompound (I) or pharmaceutically acceptable salts thereof (as describedhereinafter) will be capable of down-regulating and antagonising mutantER although it is not known at this stage whether ESR1 mutations areassociated with an altered clinical outcome.

Regardless of which resistance mechanism or combination of mechanismstakes place, many are still reliant on ER-dependent activities andremoval of the receptor through a SERD mechanism offers the best way ofremoving the ERα receptor from the cell. Fulvestrant is currently theonly SERD approved for clinical use, yet despite its mechanisticproperties, the pharmacological properties of the drug have limited itsefficacy due to the current limitation of a 500 mg monthly dose whichresults in less than 50% turnover of the receptor in patient samplescompared to the complete down-regulation of the receptor seen in invitro breast cell line experiments (Wardell, et al., Biochem. Pharm.,2011, 82:122-130).

AZD9833,N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine,optionally provided as a pharmaceutically acceptable salt thereof, hasbeen identified as a compound with the ability to act as a selectiveestrogen receptor down-regulator (SERD). AZD9833 is described as example17 in WO2018/077630A1 wherein methods for the synthesis of the compoundand its biological activity in in vitro and in vivo experiments aredisclosed. Furthermore, in contrast to the fulvestrant, the only SERDcurrently approved for clinical use, that is administered byintramuscular injection, preclinical work indicated that AZD9833 has aphysicochemical profile compatible with oral administration.

Given its favourable properties, it was envisaged that AZD9833administered orally on a daily basis might achieve superior estrogenreceptor degradation than that delivered by fulvestrant. As describedfor the first time herein, preliminary results from clinical trials ondaily oral administration of AZD9833 has led to the discovery of a rangeof doses that in heavily pre-treated patients have elicited partialresponse as established according to the RECIST criteria (for exampleaccording to RECIST 1.1 criteria, see https://recist.eortc.org/; Eur. J.Cancer 2016, 62, Pages 132-137).

SUMMARY

It is an object of the present specification to provide an appropriatedose and dosing regimen for use of AZD9833 in the treatment of cancer,for example for use in the treatment of breast cancer.

In a first aspect of the present specification there is provided AZD9833for use in the treatment of cancer where the AZD9833 is administeredorally once daily at a dose between 25 mg and 450 mg.

In a second aspect of the present specification there is provided amethod of treatment for cancer comprising administration of AZD9833 in adose between 25 mg and 450 mg once daily to a patient in need thereof.

In a third aspect of the present specification there is provided the useof AZD9833 in the manufacture of a medicament for the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg.

In a fourth aspect of the present specification there is provided apharmaceutical composition for once daily oral administration comprisingbetween 25 mg and 450 mg of AZD9833 and a pharmaceutically acceptableexcipient.

In a fifth aspect of the present specification there is provided apharmaceutical composition for once daily oral administration comprisingbetween 25 mg and 450 mg of AZD9833 and a pharmaceutically acceptableexcipient for use in the treatment of cancer.

In a sixth aspect of the present specification there is provided a kitcomprising a pharmaceutical composition comprising AZD9833 and at leastone pharmaceutically acceptable excipient and instructions for the useof the pharmaceutical composition in the treatment of cancer, where theAZD9833 is for once daily administration at a dose between 25 mg and 450mg.

FIGURES

So that the specification may be better understood, reference is made tothe following figures.

FIG. 1: Schematic of the dose-escalation phase of a phase I clinicaltrial in heavily pre-treated patients breast cancer patients suitable todemonstrate the benefits of AZD9833 treatments across the dose range.

FIG. 2: Swimmer plot of patient responses after treatment with ascendingdoses of AZD9833.

FIG. 3: Composite waterfall plot showing best change in tumor size frombaseline in patients treated with varying doses of AZD9833.

FIG. 4: Mean plasma concentration over time plot followingadministration of AZD9833 at varying doses.

DETAILED DESCRIPTION

The invention detailed in this specification should not be interpretedas being limited to any of the recited embodiments or examples. Otherembodiments will be readily apparent to a reader skilled in the art.

“A” or “an” mean “at least one”. In any embodiment where “a” or “an” areused to denote a given element, “a” or “an” may mean one. In anyembodiment where “a” or “an” are used to denote a given element, “a” or“an” may mean 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

When it is mentioned that “in some embodiments . . . ” a certain featuremay be present, the feature may be present in a suitable embodiment inany part of the specification, not just a suitable embodiment in thesame section or textual region of the specification.

Claims are embodiments.

Therapeutic Use

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg.

In one embodiment there is provided AZD9833 for use in producing ananti-proliferative effect, where the AZD9833 is administered orally oncedaily at a dose between 25 mg and 450 mg.

In one embodiment there is provided AZD9833 for selectively inhibitingERα, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg.

In one embodiment there is provided the use of AZD9833 in themanufacture of a medicament for the treatment of cancer, where theAZD9833 is administered orally once daily at a dose between 25 mg and450 mg.

In one embodiment there is provided the use of AZD9833 in themanufacture of a medicament for producing an anti-proliferative effect,where the AZD9833 is administered orally once daily at a dose between 25mg and 450 mg.

In one embodiment there is provided the use of AZD9833 in themanufacture of a medicament for selectively inhibiting ERα, where theAZD9833 is administered orally once daily at a dose between 25 mg and450 mg.

In one embodiment there is provided a method of treating cancer in ahuman or animal patient in need of such treatment, comprisingadministering to the patient AZD9833 orally once daily at a dose between25 mg and 450 mg.

In one embodiment there is provided a method of producing ananti-proliferative effect in a human or animal patient in need of suchan effect, comprising administering to the patient AZD9833 orally oncedaily at a dose between 25 mg and 450 mg.

In one embodiment there is provided a method of selectively inhibitingERα in a human or animal patient in need of such an effect, comprisingadministering to the patient AZD9833 orally once daily at a dose between25 mg and 450 mg.

Compound

In some embodiments AZD9833 may beN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amineor a pharmaceutically acceptable salt thereof.N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-aminehas the structure of compound (I) above.

In some embodiments AZD9833 may beN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine in a salt-freeform (for example in a neutral or zwitterionic form, or for example in afree base form).

In some embodiments AZD9833 may be a pharmaceutically acceptable salt ofN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine.

The term “pharmaceutically acceptable” is used to specify that an object(for example a salt, dosage form or excipient) is suitable for use inpatients. An example list of pharmaceutically acceptable salts can befound in the “Handbook of Pharmaceutical Salts: Properties, Selectionand Use”, P. H. Stahl and C. G. Wermuth, editors,Weinheim/Zurich:Wiley-VCH/VFiCA, 2002 or subsequent editions.

A suitable pharmaceutically acceptable salt ofN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amineis, for example, an acid-addition salt. An acid addition salt ofN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-aminemay be formed by bringing the compound into contact with a suitableinorganic or organic acid under conditions known to the skilled person.

An acid addition salt may for example be formed using an inorganic acidselected from hydrochloric acid, hydrobromic acid, sulphuric acid andphosphoric acid. An acid addition salt may also be formed using anorganic acid selected from acetic acid, adipic acid, benzene sulfonicacid, benzoic acid, cinnamic acid, citric acid, D,L-lactic acid, ethanedisulfonic acid, ethane sulfonic acid, fumaric acid, hydrochloric acid,L-tartaric acid, maleic acid, malic acid, malonic acid, methane sulfonicacid, napadisylic acid, phosphoric acid, saccharin, succinic acid,sulfuric acid, p-toluene sulfonic acid, toluene sulfonic acid andtrifluoroacetic acid.

A further suitable pharmaceutically acceptable salt ofN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amineis, for example, a salt formed within the human or animal body afteradministration ofN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amineto said human or animal body.

Dose Level

In some embodiments the dose of AZD9833 may be selected from 25 mg, 75mg, 150 mg, 300 mg and 450 mg.

In some embodiments the dose of AZD9833 may be 25 mg.

In some embodiments the dose of AZD9833 may be 75 mg.

In some embodiments the dose of AZD9833 may be 150 mg.

In some embodiments the dose of AZD9833 may be 300 mg.

In some embodiments the dose of AZD9833 may be 450 mg.

In some embodiments the dose of AZD9833 may be an oral daily dose.

An “oral daily dose” is the amount of AZD9833 administered by mouth in a24-hour period.

In some embodiments the AZD9833 may be administered as a single dose.

In some embodiments the AZD9833 may be administered as a divided dose.

A “divided dose” is one where the total dose (for example the oral dailydose) is administered in multiple (for example 1, 2, 3, 4 or 5)portions.

In some embodiments the AZD9833 may be administered as a single doseunit or as multiple dose units.

A “dose unit” is a discrete dosage form, for example a specified number(for example 1, 2, 3, 4 or 5) of tablets or capsules.

In some embodiments the AZD9833 may be administered as a single tablet.

In some embodiments the AZD9833 may be administered as a single tabletonce daily.

In some embodiments the AZD9833 may be administered orally as a singletablet once daily.

For the avoidance of doubt, when a range of doses for AZD9833 ispresented herein, for example, a dose between 25 mg and 450 mg, therange includes the doses at the endpoints of the range as well as dosesfalling in between those endpoints, i.e. 25 mg and 450 mg and quantitiesin between.

Cancer

“Cancer” is used synonymously with tumor and lesion in thisspecification. Cancer may include primary cancer as well as secondarycancers and metastases.

The “treatment of cancer”, “treating cancer” and similar terms encompasstreating an existing cancer and/or preventing cancer.

In some embodiments the treatment of cancer or treating cancer may meantreating and preventing cancer.

In some embodiments the treatment of cancer or treating cancer may meantreating cancer.

In some embodiments the treatment of cancer or treating cancer may meanpreventing cancer.

In some embodiments cancer may be selected from breast cancer andgynaecological cancer.

“Gynaecological cancer” includes womb cancer, ovarian cancer, cervicalcancer, vulva cancer and vaginal cancer.

In some embodiments cancer may be selected from breast cancer, wombcancer, ovarian cancer, cervical cancer, vulva cancer and vaginalcancer.

In some embodiments cancer may be ER-positive HER2-negative breastcancer.

“ER-positive HER2-negative breast cancer” comprises tumors with estrogenreceptors (are ER-positive) that do not have high levels of the HER2gene or the HER2 protein (are HER2-negative). ER-positive andHER2-negative status can be determined by methods known in the art,including the use of commercial kits.

In some embodiments breast cancer may be ER-positive breast cancer.

In some embodiments breast cancer may be HER2-negative breast cancer.

In some embodiments cancer may be ER-positive HER2-negative advancedbreast cancer.

In some embodiments breast cancer may be ER-positive advanced breastcancer.

In some embodiments breast cancer may be HER2-negative advanced breastcancer.

Patient Selection

In some embodiments AZD9833 may be administered to a pre- orpost-menopausal woman.

In some embodiments AZD9833 may be administered to a pre-menopausalwoman.

In some embodiments AZD9833 may be administered to a post-menopausalwoman.

In some embodiments AZD9833 may be administered to a pre- orpost-menopausal woman whose cancer is ER-positive.

In some embodiments AZD9833 may be administered to a pre- orpost-menopausal woman whose cancer is HER2-negative.

In some embodiments AZD9833 may be administered to a pre- orpost-menopausal woman whose cancer is ER-positive and HER2-negative.

In some embodiments AZD9833 may be administered to a pre- orpost-menopausal woman whose cancer has an ESR1 mutation.

In some embodiments AZD9833 may be administered to a pre- orpost-menopausal woman whose cancer does not have an ESR1 mutation.

In some embodiments AZD9833 may be administered to a patient whosecancer has previously been treated with between 1 and 15 anti-cancertherapies.

In some embodiments AZD9833 may be administered to a patient whosecancer has previously been treated with between 1 and 10 anti-cancertherapies.

In some embodiments AZD9833 may be administered to a patient whosecancer has previously been treated with between 1 and 5 anti-cancertherapies.

In some embodiments AZD9833 may be administered to a patient whosecancer has previously been treated with between 5 and 10 anti-cancertherapies.

Where a patient has “previously been treated”, this refers to anytreatment administered to the patient prior to them being dosed withAZD9833. Previous treatment does not imply that the therapy in questionwas successful or curative, only that a patient received treatment withthe therapy (for example, as a result of being prescribed the therapy bya suitably qualified healthcare professional).

“Anti-cancer therapies” include medicaments, drugs, compounds or othermedical approaches (for example treatments using a patient's ownimmunological agents) aimed at the treatment of cancer. Exampleanti-cancer therapies are endocrine therapies and chemotherapies.

“Endocrine therapies” are those which work by modulating a patient'shormonal pathways. Examples include estrogen inhibitors (such astamoxifen or fulvestrant), aromatase inhibitors (such as letrozole,anastrozole, vorazole or exemestane), progestogens (such as megestrolacetate) and luteinising hormone blockers (such as leuprolide orgoserelin).

“Chemotherapies” are cancer therapies which are not endocrine therapies.They include for example:

-   -   i. Traditional antiproliferative/antineoplastic drugs and        combinations thereof, including alkylating agents (for example        cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen        mustard, melphalan, chlorambucil, busulphan, temozolomide and        nitrosoureas); antimetabolites (for example gemcitabine and        antifolates such as fluoropyrimidines like 5-fluorouracil and        tegafur, raltitrexed, methotrexate, cytosine arabinoside, and        hydroxyurea); antitumor antibiotics (for example anthracyclines        like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,        idarubicin, mitomycin-C, dactinomycin and mithramycin);        antimitotic agents (for example vinca alkaloids like        vincristine, vinblastine, vindesine and vinorelbine and taxoids        like taxol and taxotere and polokinase inhibitors); and        topoisomerase inhibitors (for example epipodophyllotoxins like        etoposide and tenoposide, amsacrine, topotecan and        camptothecin);    -   ii. Inhibitors of growth factor function and their downstream        signalling pathways, including Ab modulators of any growth        factor or growth factor receptor targets, as for example        reviewed by Stern et al. Critical Reviews in        Oncology/Haematology, 2005, 54, pp 11-29; small molecule        inhibitors of such targets, for example kinase inhibitors.        Specific examples include the anti erbB2 antibodies trastuzumab        [Herceptin™] and pertuzumab [Perjeta™], the HER-2 directed        antibody-drug conjugates trastuzumab deruxtecan [Enhertu™] and        trastuzumab emtansine [Kadcyla™], the anti-EGFR antibody        panitumumab, the anti EGFR antibody cetuximab (Erbitux, C225)        and tyrosine kinase inhibitors including inhibitors of the erbB        receptor family, such as epidermal growth factor family receptor        (EGFR/erbB1), tyrosine kinase inhibitors such as gefitinib,        osimertinib or erlotinib, erbB2 tyrosine kinase inhibitors such        as lapatinib, and mixed erb1/2 inhibitors such as afatinib.        Other example classes of growth factors and their receptor        modulators include for example inhibitors of the hepatocyte        growth factor family or their receptors (including c-met and        ron); inhibitors of the insulin and insulin growth factor family        or their receptors (IGFR, IR), inhibitors of the        platelet-derived growth factor (PDGFR) family or their receptors        and inhibitors of signalling mediated by other receptor tyrosine        kinases such as c-kit, AnLK, and CSF-1R; modulators which target        signalling proteins in the PI3-kinase signalling pathway, for        example, inhibitors of PI3-kinase isoforms such as PI3K-α,        PI3K-β. PI3K-γ and PI3K-δ and ser/thr kinases such as AKT (such        as capivasertib, afuresertib, miransertib, ARQ751, ipataserib,        MK-2206 or perifosine), mTOR (such as AZD2014 or everolimus),        PDK, SGK, PI4K or PIP5K; inhibitors of serine/threonine kinases        not listed above, for example raf inhibitors such as        vemurafenib, MEK inhibitors such as selumetinib (AZD6244), AbI        inhibitors such as imatinib or nilotinib, Btk inhibitors such as        ibrutinib, acalabrutinib, and zanubrutinib, Syk inhibitors such        as fostamatinib, aurora kinase inhibitors (for example AZD1152),        inhibitors of other ser/thr kinases such as JAKs, STATs and        IRAK4, and cyclin dependent kinase inhibitors for example        inhibitors of CDK1, CDK4, CDK6, CDK7, CDK9 and CDK4/6 (such as        palbociclib, ribociclib, abemaciclib, lerociclib and        trilaciclib);    -   iii. Modulators of DNA damage signalling pathways, for example        PARP inhibitors (e.g. olaparib, rucaparib, niraparib and        talazoparib), ATR inhibitors (such as AZD6738) or ATM        inhibitors;    -   iv. Modulators of apoptotic and cell death pathways such as BCI        family modulators (e.g. ABT-263/Navitoclax, ABT-199);    -   v. Antiangiogenic agents such as those which inhibit the effects        of vascular endothelial growth factor, for example the        anti-vascular endothelial cell growth factor antibody        bevacizumab (Avastin™) or a VEGF receptor tyrosine kinase        inhibitor such as sorafenib, axitinib, pazopanib, sunitinib or        vandetanib (and compounds that work by other mechanisms (for        example linomide, inhibitors of integrin function and        angiostatin);    -   vi. Vascular damaging agents, such as Combretastatin A4;    -   vii. Anti-invasion agents, for example c-Src kinase family        inhibitors like (dasatinib, J. Med. Chem., 2004, 47, 6658-6661)        and bosutinib (SKI-606), and metalloproteinase inhibitors like        marimastat, inhibitors of urokinase plasminogen activator        receptor function or antibodies to heparanase);    -   viii. Immunotherapy, including for example ex vivo and in vivo        approaches to increase the immunogenicity of patient tumor        cells, such as transfection with cytokines such as interleukin        2, interleukin 4 or granulocyte macrophage colony stimulating        factor, approaches to decrease T-cell anergy, approaches using        transfected immune cells such as cytokine transfected dendritic        cells, approaches using cytokine transfected tumor cell lines        and approaches using anti idiotypic antibodies. Specific        examples include monoclonal antibodies targeting PD-1 (e.g.        pembrolizumab, nivolumab, cemiplimab), PD-L1 (e.g. durvalumab,        atezolizumab or avelumab) or CTLA4 (e.g. ipilimumab and        tremelimumab);    -   ix. Antisense or RNAi based therapies, for example those which        are directed to the targets listed in this specification; and    -   x. Gene therapy approaches, including for example approaches to        replace aberrant genes such as aberrant p53 or aberrant BRCA1 or        BRCA2, GDEPT (gene directed enzyme pro drug therapy), approaches        such as those using cytosine deaminase, thymidine kinase or a        bacterial nitro reductase enzyme and approaches to increase        patient tolerance to chemotherapy or radiotherapy such as multi        drug resistance gene therapy.

In some embodiments AZD9833 may be administered to a patient whosecancer has previously been treated with ≥1 endocrine therapy and ≤2chemotherapies.

In some embodiments AZD9833 may be administered to a patient whosecancer has previously been treated with ≥1 endocrine therapy and ≤2chemotherapies for ER-positive HER2-negative breast cancer.

“Chemotherapies for ER-positive HER2-negative breast cancer” may includeany anti-cancer regimen(s) comprising at least one cytotoxic agent givenfor 21 days or longer.

In some embodiments AZD9833 may be administered to a patient whosecancer has previously been treated with ≥1 endocrine therapy and ≤2chemotherapies for ER-positive HER2-negative advanced breast cancer.

In some embodiments the ≥1 endocrine therapy may be selected from anestrogen inhibitor, an aromatase inhibitor, a progestogen and aluteinising hormone blocker.

In some embodiments the ≥1 endocrine therapy may be selected fromtamoxifen, toremifene, raloxifene, droloxifene, idoxifene, fulvestrant,letrozole, anastrozole, vorazole, exemestane, megestrol acetate,leuprolide and goserelin.

In some embodiments the ≤2 chemotherapies may be selected from a CDKinhibitor (such as a CD4, CDK6, or CDK4/CDK6 dual inhibitor) and an mTORinhibitor.

In some embodiments the ≤2 chemotherapies may be selected frompalbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib andeverolimus.

In some embodiments AZD9833 may be administered to a patient whosecancer is resistant to aromatase inhibitors.

In some embodiments AZD9833 may be administered to a patient whosecancer is resistant to non-steroidal aromatase inhibitors.

In some embodiments AZD9833 may be administered to a patient whosecancer is resistant to an aromatase inhibitor selected from letrozoleand anastrozole.

When a patient's cancer is “resistant” (or refractory) to a particulardrug or therapy, the cancer no longer responds sufficiently to treatmentfor it to be considered a suitable medical option going forward, suchthat an attending physician recommends a different therapeutic approach.

In some embodiments AZD9833 may be administered to a patient whosecancer is resistant to tamoxifen.

In some embodiments AZD9833 may be administered to a patient whosecancer is resistant to fulvestrant.

In some embodiments AZD9833 may be administered to a patient whosecancer is resistant to CDK inhibitors.

Pharmacokinetic and Pharmacodynamic Properties

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg and achieves a mean peak blood plasmaconcentration in a cancer patient of between 10 and 1000 ng/mL.

The “peak mean blood plasma concentration” refers to the maximum amountof AZD9833 achieved in a patient's plasma following treatment.

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg and achieves a median terminal half-life ofbetween 8 h and 14 h in a cancer patient.

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg and achieves a median terminal half-life of 12h in a cancer patient.

The “median terminal half-life” is the median time for a patient's drugblood plasma concentration to halve after reaching pseudo-equilibrium.

Clinical Properties

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg and achieves an objective response rate between10% and 20%.

“Objective response rate” is the percentage of patients with measurabledisease at baseline and who have a date of first dose of 217 weeks or adate of post-treatment scan of 215 weeks that indicates a confirmedresponse as measured by the RECIST criteria.

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg and achieves a clinical benefit rate between25% and 100%.

“Clinical benefit rate” is the percentage of patients who have a date offirst dose of 225 weeks or a date of post-treatment scan of 223 weeksthat indicates a confirmed response or stable disease as measured by theRECIST criteria for >23 weeks post treatment.

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg and achieves a clinical benefit rate greaterthan 25%.

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg and achieves a clinical benefit rate between25% and 90%.

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg and achieves a clinical benefit rate between25% and 80%.

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg and achieves a clinical benefit rate between25% and 75%.

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg and does not cause any serious side-effects ina cancer patient.

In some embodiments serious side-effects may be defined as grade 4 or 5adverse events.

“Grade 4 or 5 adverse events” can be classified according to the commonterminology criteria for adverse events (CTCAE).

Combination Treatment

In one embodiment there is provided AZD9833 for use in the treatment ofcancer, where the AZD9833 is administered orally once daily at a dosebetween 25 mg and 450 mg in combination with a further anti-cancertherapy.

When a drug is administered “in combination” with AZD9833, thecombination may comprise the separate, sequential, or simultaneousadministration of the drugs. Where treatment is separate and/orsequential, the interval between the dose of AZD9833 and the dose of thefurther anti-cancer therapy may be chosen to ensure the production of acombined therapeutic effect.

In some embodiments the administration of the AZD9833 and a furtheranti-cancer therapy is separate.

In some embodiments the administration of the AZD9833 and a furtheranti-cancer therapy is sequential.

In some embodiments the administration of the AZD9833 and a furtheranti-cancer therapy is separate and sequential.

In some embodiments the further anti-cancer therapy may be a CDKinhibitor.

In some embodiments the further anti-cancer therapy may be a CDK4inhibitor.

In some embodiments the further anti-cancer therapy may be a CDK6inhibitor.

In some embodiments the further anti-cancer therapy may be a dualCDK4/CDK6 inhibitor.

In some embodiments the further anti-cancer therapy may be a CDKinhibitor selected from palbociclib, ribociclib, abemaciclib, lerociclibor trilaciclib.

In some embodiments the further anti-cancer therapy may be palbociclib.

In some embodiments the further anti-cancer therapy may be an mTORinhibitor.

In some embodiments the further anti-cancer therapy may be an mTORinhibitor selected from sirolimus, deforolimus, everolimus andtemsirolimus.

In some embodiments the further anti-cancer therapy may be everolimus.

In some embodiments the further anti-cancer therapy may be everolimuswhich is administered orally once daily at a dose of up to 10 mg.

In some embodiments the further anti-cancer therapy may be selected frompalbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib andeverolimus.

In some embodiments the further anti-cancer therapy may be selected frompalbociclib, ribociclib, abemaciclib, lerociclib and trilaciclib.

In some embodiments the further anti-cancer therapy may be an AKTinhibitor.

In some embodiments the further anti-cancer therapy may be selected fromcapivasertib, afuresertib, miransertib, ARQ751, ipataserib, MK-2206 orperifosine.

Compositions

In one embodiment there is provided a composition for once daily oraladministration comprising between 25 mg and 450 mg of AZD9833 and apharmaceutically acceptable excipient.

In some embodiments pharmaceutically acceptable excipients may beselected from inert diluents (for example microcrystalline cellulose ordicalcium phosphate anhydrous), granulating agents, disintegratingagents (for example sodium starch glycolate), binding agents,lubricating agents (for example magnesium stearate), preservativeagents, antioxidants and chelating agents.

In some embodiments the composition for once daily oral administrationcomprises between 25 mg and 450 mg of AZD9833, for example 25 mg, 75 mgor 100 mg of AZD9833, and at least one diluent selected frommicrocrystalline cellulose (MCC), dicalcium phosphate anhydrous (DCPA),mannitol, lactose, dicalcium phosphate, calcium sulfate dihydrate,tribasic calcium phosphate, dibasic calcium phosphates dihydrate,silicified microcrystalline cellulose, their co-processed combinations,polydextrose, trehalose, sucrose, glucose, cyclodextrin andhydroxypropyl cellulose.

The composition for once daily oral administration may further compriseat least one disintegrant selected from croscarmellose sodium,crospovidone, sodium starch glycolate (SSG) and low substitutedhydroxypropyl cellulose (L-HPC).

The composition for once daily oral administration may further compriseat least one lubricant selected from magnesium stearate, calciumstearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate andstearic acid.

Dosage Forms

In one embodiment there is provided a pharmaceutical compositioncomprising between 25 mg and 450 mg of AZD9833 and a pharmaceuticallyacceptable excipient in the form of a tablet or a capsule for once dailyoral administration.

Tablet formulations may be uncoated or coated either to modify theirdisintegration and the subsequent absorption of the active ingredientwithin the gastrointestinal tract, or to improve their stability and/orappearance, in either case, using conventional coating agents andprocedures known in the art. For example, tablet formulations may betreated such that they release active ingredients immediately.

In one embodiment there is provided a pharmaceutical compositioncomprising between 25 mg and 450 mg of AZD9833, for example between 25and 100 mg of AZD9833, and a pharmaceutically acceptable excipient,which composition is an immediate release composition.

In one embodiment there is provided a pharmaceutical compositioncomprising between 25 mg and 450 mg of AZD9833, for example between 25and 100 mg of AZD9833, and a pharmaceutically acceptable excipient inthe form of a single tablet for once daily oral administration.

As well as tablets, compositions for oral use may alternatively be inthe form of hard gelatine capsules in which the active ingredient ismixed with an inert solid diluent, or as soft gelatine capsules in whichthe active ingredient is mixed with water or an oil.

In one embodiment there is provided a pharmaceutical compositioncomprising between 25 mg and 450 mg of AZD9833, for example between 25and 100 mg of AZD9833, and a pharmaceutically acceptable excipient inthe form of a single capsule for once daily oral administration.

In one embodiment there is provided the use of a pharmaceuticalcomposition comprising between 25 mg and 450 mg of AZD9833, for examplebetween 25 and 100 mg of AZD9833, and a pharmaceutically acceptableexcipient in the treatment of cancer, where the pharmaceuticalcomposition is administered once daily.

Kits

In one embodiment there is provided a kit comprising a pharmaceuticalcomposition comprising AZD9833 and at least one pharmaceuticallyacceptable excipient and instructions for the use of the pharmaceuticalcomposition in the treatment of cancer, where the AZD9833 is for oncedaily administration at a dose between 25 mg and 450 mg.

In one embodiment there is provided a kit comprising:

-   -   a pharmaceutical composition comprising AZD9833 and at least one        pharmaceutically acceptable excipient;    -   an additional anti-cancer agent for administration in        combination with AZD9833; and    -   instructions for the use of the pharmaceutical composition in        the treatment of cancer, where the AZD9833 is for once daily        administration at a dose between 25 mg and 450 mg.

In one embodiment there is provided a kit comprising:

-   -   a pharmaceutical composition comprising AZD9833 and at least one        pharmaceutically acceptable excipient;    -   an additional anti-cancer agent for administration in        combination with AZD9833; and    -   instructions for the use of the pharmaceutical composition in        the treatment of cancer, where the AZD9833 is for once daily        administration at a dose between 25 mg and 450 mg.

In one embodiment there is provided a kit comprising:

-   -   a pharmaceutical composition comprising AZD9833 and at least one        pharmaceutically acceptable excipient;    -   an additional anti-cancer agent selected from palbociclib,        ribociclib, abemaciclib or trilaciclib for administration in        combination with AZD9833; and    -   instructions for the use of the pharmaceutical composition in        the treatment of cancer, where the AZD9833 is for once daily        administration at a dose between 25 mg and 450 mg.

Examples Clinical Trial Protocol

Introduction:

To determine the optimal dosing regimen for AZD9833 Phase 1dose-escalation and expansion in patients with ER positive, HER2negative advanced breast cancer was carried out according to thefollowing basic protocol.

Rationale:

AZD9833 has the potential to provide superior clinical benefit toexisting endocrine therapies through enhanced bioavailability (comparedto fulvestrant, which is administered intramuscularly) and target(estrogen receptor) engagement and modulation in patients with estrogenreceptor positive (ER+) breast cancer. The study's primary objective isto determine the safety and tolerability of AZD9833 in women with ER+human epidermal growth factor receptor 2 negative (HER2-) advancedbreast cancer. In addition, the pharmacokinetics and preliminaryanti-tumour activity of AZD9833 will be investigated.

Primary Objectives and Endpoints:

TABLE 1 Primary/Safety Objective Primary Endpoints/Variables Toinvestigate the safety and Dose-limiting toxicities (DLTs). tolerabilityof AZD9833 in women Adverse events (AEs)/serious with estrogen receptorpositive adverse events (SAEs). (ER+) human epidermal growth Vitalsigns. factor receptor 2 negative Clinical chemistry/haematology (HER2−)advanced breast cancer parameters. to define the doses and Triplicateelectrocardiograms schedules for further clinical (ECGs) evaluation ofAZD9833 as a monotherapy.

Secondary Objectives and Endpoints:

TABLE 2 Secondary Objective Primary Endpoints/Variables To assess theanti-tumour According to the Response activity and efficacy ofEvaluation Criteria in AZD9833 as a monotherapy. Solid Tumour (RECIST)1.1 by investigator assessment: Objective response rate (ORR) Durationof response (DoR) Clinical benefit rate at 24 weeks (CBR 24weeks)Percentage change in tumour size Progression-free survival (PFS). Tocharacterise the Plasma and urine AZD9833 single- and multiple-doseconcentrations and derived pharmacokinetics of pharmacokineticparameters. AZD9833. To investigate AZD9833 activity Assessment ofbiomarker in tumour cells. changes, which include expression levels ofestrogen receptor (ER), progesterone receptor (PgR) and Ki67 protein.

Exploratory Objectives and Endpoints:

TABLE 3 Secondary Objective Primary Endpoints/Variables To investigateAZD9833 Assessment of exploratory activity in tumour, biomarker changes,which circulating tumour cells may include but are not (CTCs), andblood, limited to expression including plasma levels of estrogencirculating tumour DNA receptor-regulated gene (ctDNA). expression, andgene mutational status. To investigate predictive Mutational status ofmarkers of response and/or cancer-associated genes acquired resistancein tumour and ctDNA. to AZD9833 in Assessment of tumour, blood, andexploratory blood borne plasma ctDNA. biomarkers, including but notlimited to gene expression. To perform future Exploratory tumour andexploratory research of circulating biomarkers. biomarkers that mayinfluence development of breast cancer and/or response to treatment. Tocollect and store DNA Possible future genetic according to eachcountry's research.Results may be local and ethical procedures reportedoutside this for future exploratory study's CSR. research intogenes/genetic variation that may influence response to treatment. Toinvestigate any change in Changes in the4β-hydroxycholesterol/cholesterol 4β-hydroxycholesterol/cholesterolratio as a marker of cytochrome ratio vs baseline. P450 3A4 (CYP3A4)induction by AZD9833. To investigate any change in Changes in the4β-hydroxycholesterol/cholesterol 4β-hydroxycholesterol/cholesterolratio as a marker of cytochrome ratio vs baseline. P450 3A4 (CYP3A4)induction by AZD9833. To investigate the effect of Exploratoryassessment of AZD9833 on ECG and blood pressure, cardiovascularparameters. echocardiogram and ECG data, the latter to include bothtriplicate and continuously acquired, and of methodologies to calculateQTc

Overall Design:

This is a multicentre dose escalation and expansion, first-in-humanstudy designed to evaluate the safety and tolerability of AZD9833 alone(Parts A and B) in women with endocrine-resistant ER+ HER2− breastcancer that is not amenable to treatment with curative intent.

Part A of the study allow for dose escalation of AZD9833 alone. Forthese parts, a ‘cohort’ will constitute all the patients dosed at thatparticular dose level in the dose escalation scheme as illustrated inFIG. 1. In Part B of the study (expansion), eligible subjects will berandomised to receive selected doses of AZD9833 based on the findings inPart A.

Throughout the study, pre-menopausal subjects will take AZD9833 with abackground of a LHRH agonist (see Background Medication).

Part A:

Eligible pre- and post-menopausal subjects will receive AZD9833. Forinitial dosing, the first patient in each cohort will be followed to Day8 before further patients are allocated to that dose level cohort; seeSection 6.1.5.5. When there are sufficient evaluable subjects for adecision regarding dose escalation (between 3 and 6 subjects), thecohort may be optionally expanded to include additional subjects (tohave up to 12 evaluable subjects in a cohort) and/or a cohort may beopened at the next dose level. A maximum of 8 dose-level cohorts isanticipated in Part A of the study. Escalation will stop at the MTD/MFD.Part A will include at least 2 subjects with paired tumour biopsies ateach dose level.

The dose escalation phase of the study will determine the MTD or MFD ofAZD9833 based on the assessment of the safety, tolerability, and PK datacollected during the first 28 days of daily dosing. The dose escalationand de-escalation plan for evaluating AZD9833 will follow a Bayesianadaptive design scheme (Neuenschwander et al., Stat Med. 2008, 15:2420),which combines prior expectations about the dose-toxicity relationshipand applies the data at the end of each cohort to recommend a dose forthe next cohort. Once safety and tolerability have been establishedfollowing at least 7 days of treatment of the first subject in each doselevel cohort, up to 3 additional subjects will be enrolled to ensure atleast 3 evaluable subjects at 28 days.

Optional expansions during the dose escalation are included at AZD9833doses where those doses have a pre-clinically predicted pharmacodynamiceffect on ER greater than or equal to fulvestrant, a reasonable standardof care in this disease setting. This will provide an early opportunityfor subjects to receive the drug at potentially therapeutic doses and topermit further investigation of the safety, tolerability, and thepharmacologic and biological activity profile of AZD9833. Dose level(s)to be expanded will be based on emerging data and will be approved bythe Safety Review Committee (SRC).

The expansion of Part A of the study also provides for the recruitmentof at least 2 subjects suitable for paired on-study tumour biopsies toenable a preliminary assessment of tumour pharmacodynamics across awider range of doses than will be examined in Part B.

Part B:

Eligible pre-menopausal (n=12) subjects will receive AZD9833 300 mg (thehighest of the three selected dose levels from Part A) andpost-menopausal (n=36) subjects will be randomised 1:1:1 to receiveeither AZD9833 300 mg, AZD9833 150 mg or AZD9833 75 mg. Part B willinclude at least 5 paired biopsy-evaluable subjects in each of the 4treatment groups (pre-menopausal dose 300 mg, post-menopausal dose 300mg, post-menopausal dose 150 mg, post-menopausal dose 75 mg).

Part B will permit further evaluation of the safety profile of AZD9833in a larger group of post-menopausal subjects at 3 distinct dose levels.The objective of the examination of 3 dose levels is to permit a robustselection of recommended doses for further clinical exploration infuture AZD9833 studies, both in the advanced breast cancer setting and,potentially, in the early disease/adjuvant setting. A randomised designis applied to the allocation of 36 subjects to 1 of 3 tolerated doselevels from part A, to facilitate a robust comparison of the safetyprofile by avoiding allocation or any other potential experimental bias.Part B will also allow for up to 12 pre-menopausal subjects to beallocated to the highest of the 3 doses considered safe and welltolerated in Part A (300 mg).

Part B also includes provision for the recruitment of a subset (n=15post-menopausal, that is 5 at each dose level and n=5 pre-menopausal ata dose level of 300 mg) of subjects suitable for paired on-study tumourbiopsies to enable further assessment of tumour pharmacodynamics.

Study Population:

Prospective approval of protocol deviations to recruitment and enrolmentcriteria, also known as protocol waivers or exemptions, is notpermitted. Each subject should meet all of the inclusion criteria andnone of the exclusion criteria to be assigned/randomised to AZD9833.Under no circumstances can there be exceptions to this rule. Subjectswho do not meet the entry requirements are screen failures.

Enrolled subjects are defined as those who sign informed consent.Treated subjects are those who receive at least 1 dose of AZD9833. InParts B and D, enrolled subjects are randomised into their treatmentgroup. Randomised subjects are defined as those who undergorandomisation and receive a randomisation number.

Inclusion Criteria:

Patients are eligible to be included in the study only if all of thefollowing inclusion criteria and none of the exclusion criteria apply:

-   -   1. Provision of signed and dated written informed consent prior        to any mandatory study-specific procedures, sampling, and        analyses. If a subject declines to participate in any voluntary        exploratory research and/or genetic component of the study,        there will be no penalty or loss of benefit to the subject and        she will not be excluded from other aspects of the study.    -   2. Aged at least 18 years.    -   3. Menopausal status as follows:        -   (a) Pre-menopausal women must have commenced treatment with            an LHRH agonist at least 4 weeks prior to starting AZD9833            and must be willing to continue to receive LHRH agonist            therapy for the duration of the study.        -   (b) Post-menopausal defined as meeting at least 1 of the            following criteria:            -   (i) Have undergone a bilateral oophorectomy.            -   (ii) Age ≥60 years.            -   (iii) Age ≥50 years and with cessation of regular menses                ≥12 months and with an intact uterus in the absence of                oral contraception or hormone replacement therapy prior                to the diagnosis of breast cancer.            -   (iv) Age <60 years and with cessation of regular menses                212 months and follicle-stimulating hormone (FSH) and                oestradiol levels in the postmenopausal range (utilising                ranges from the local laboratory facility).        -   (c) Those not meeting the definition for post-menopausal are            regarded as pre-menopausal.    -   4. Histological or cytological confirmation of adenocarcinoma of        the breast.    -   5. Documented positive estrogen receptor status of primary or        metastatic tumour tissue, according to the local laboratory        parameters and where those laboratory parameters are in        accordance with accepted diagnostic guidelines, e.g. American        Society of Clinical Oncology/College of American Pathologists        Guideline Recommendations for Immunohistochemical Testing of        Estrogen and Progesterone Receptors in Breast Cancer (Hammond        et. al. 2010). HER2− defined as an immunohistochemistry (IHC)        Score 0 or 1+ or negative by in situ hybridisation (ISH;        FISH/CISH/SISH); if IHC 2+, ISH negativity is required. Where        available, assessment of ER and HER2 status should be based on        the most recent tumour biopsy sample.    -   6. Metastatic disease or locoregionally recurrent disease which        is refractory or intolerant to existing therapy(ies) known to        provide clinical benefit.    -   7. Prior chemotherapy, endocrine therapy and other therapy as        follows:        -   (a) No more than 2 lines of chemotherapy for advanced            disease.        -   (b) Recurrence or progression on at least one line of            endocrine therapy in the advanced/metastatic disease            setting.        -   (c) There is no limit on the number of lines of prior            endocrine therapies.        -   (d) Prior treatment with CDK4/6 inhibitors is permitted.    -    A chemotherapy line in advanced disease is an anticancer        regimen(s) that contains at least one cytotoxic chemotherapy        agent and given for 21 days or longer. If a cytotoxic        chemotherapy regimen was discontinued for a reason other than        disease progression and lasted less than 21 days, then this        regimen does not count as a prior line of chemotherapy. Repeat        administration of the same anti-cancer regimen on a separate        occasion does not count as a new line of chemotherapy.    -   8. Metastatic disease or locoregionally recurrent disease which        is refractory or intolerant to existing therapy(ies) known to        provide clinical benefit.    -   9. Women of childbearing potential must agree to use one highly        effective contraceptive measure (as defined in Section 5.3.1        Contraceptive Measures) from the time of screening until 4 weeks        after discontinuing AZD9833, must not be breast feeding, and        must have a negative pregnancy test prior to the start of        dosing.    -   10. At least one lesion (measurable and/or non-measurable, as        per Response Evaluation Criteria in Solid Tumours version 1.1        [RECIST 1.1] that can be accurately assessed at baseline and is        suitable for repeated assessment by computed tomography (CT),        magnetic resonance imaging (MRI), or plain X-ray; or clinical        examination. Blastic-only lesions in bone are not considered        assessable.    -   11. Eastern Cooperative Oncology Group (ECOG)/World Health        Organization (WHO) performance status 0 to 1, with no        deterioration over the previous 2 weeks and a minimum life        expectancy of 12 weeks.

Exclusion Criteria:

Patients must not enter the study if any of the following exclusioncriteria are fulfilled:

-   -   1. Intervention with any of the following:        -   (a) Any cytotoxic chemotherapy, investigational agents or            other anti-cancer drugs for the treatment of advanced breast            cancer from a previous treatment regimen or clinical study            within 14 days of the first dose of AZD9833.        -   (b) Medications or herbal supplements known to be strong            inhibitors/inducers of cytochrome P450 3A4/5 (CYP3A4/5) and            sensitive cytochrome P450 216 (CYP2B6) substrates (commonly            prescribed drugs are listed in Appendix B), or inability to            stop use within the washout period as specified in Appendix            B prior to receiving the first dose of AZD9833.        -   (c) Drugs that are known to prolong QT and have a known risk            of Torsades de Pointes.        -   (d) Radiotherapy with a limited field of radiation for            palliation within 1 week of the first dose of AZD9833, with            the exception of patients receiving radiation to more than            30% of the bone marrow or a wide field of radiation within 4            weeks of the first dose of AZD9833.        -   (e) Major surgical procedure or significant traumatic            injury, as judged by the investigator, within 4 weeks of the            first dose of AZD9833, or an anticipated need for major            surgery and/or any surgery requiring general anaesthesia            during the study.    -   2. Any unresolved toxicities from prior therapy greater than        Common Terminology Criteria for Adverse Events (CTCAE) Grade 1        at the time of starting AZD9833, with the exception of alopecia.    -   3. Presence of life-threatening metastatic visceral disease, as        judged by the investigator, uncontrolled central nervous system        (CNS) metastatic disease. Patients with spinal cord compression        and/or brain metastases may be enrolled if definitively treated        (e. g., surgery or radiotherapy) and stable off steroids for at        least 4 weeks prior to start of AZD9833.    -   4. Any evidence of severe or uncontrolled systemic diseases,        including uncontrolled hypertension and active bleeding        diatheses, or e.g., infection requiring intravenous antibiotic        therapy, which in the investigator's opinion makes it        undesirable for the patient to participate in the study or which        would jeopardise compliance with the protocol, or active        infection (requiring antiviral treatment) including hepatitis B,        hepatitis C, and human immunodeficiency virus (HIV).    -   5. Any of the following cardiac criteria:        -   (a) Mean resting QT interval corrected by Fridericia's            formula (QTcF)>470 msec obtained from a triplicate            electrocardiogram (ECG).        -   (b) Any clinically important abnormalities in rhythm,            conduction, or morphology of resting ECG (ego, complete left            bundle branch block, second- and third-degree heart block),            or clinically significant sinus pause. Patients with            controlled atrial fibrillation can be enrolled.        -   (c) Any factors that increase the risk of QTc prolongation            or risk of arrhythmic events such as symptomatic heart            failure, hypokalaemia, congenital long QT syndrome,            immediate family history of long QT syndrome, or unexplained            sudden death at <40 years of age. Hypertrophic            cardiomyopathy and clinically significant stenotic valve            disease.        -   (d) Experience of any of the following procedures or            conditions in the preceding 6 months: coronary artery bypass            graft, angioplasty, vascular stent, myocardial infarction,            unstable angina pectoris, congestive heart failure New York            Heart Association (NYHA) Grade 22, cerebrovascular accident,            or transient ischaemic attack.        -   (e) Uncontrolled hypertension. Hypertensive patients may be            eligible, but blood pressure must be adequately controlled            at baseline. Patients may be re-screened regarding the blood            pressure requirement.    -   6. Inadequate bone marrow reserve or organ function as        demonstrated by any of the following laboratory values:        -   (a) Absolute neutrophil count (ANC)<1.5×10 9/L        -   (b) Platelet count <100×10 9/L        -   (c) Haemoglobin <90 g/L        -   (d) Alanine aminotransferase (ALT)>2.5× the upper limit of            normal (ULN).        -   (e) Aspartate aminotransferase (AST)>2.5×ULN.        -   (f) Total bilirubin (TBL)>1.5×ULN or >3×ULN in the presence            of documented Gilbert's Syndrome (unconjugated            hyperbilirubinaemia).        -   (g) Glomerular filtration rate (GFR)<50 ml/min.    -   7. Involvement in the planning and conduct of the study.    -   8. Refractory nausea and vomiting, uncontrolled chronic        gastrointestinal (GI) diseases, inability to swallow the        formulated product, or previous significant bowel resection that        would preclude adequate absorption of AZD9833. History of        hypersensitivity to active or inactive excipients of AZD9833 or        drugs with a similar chemical structure or class to AZD9833.    -   9. Judgment by the investigator that the patient should not        participate in the study if the patient is unlikely to comply        with study procedures, restrictions, and requirements.    -   10. Male subjects are excluded from this study.

Study Treatments:

AZD9833, administered as 25 mg and 100 mg tablets. AZD9833 will beadministered as an oral dose, initially once daily. It should be takenin the morning, with or without food, at approximately the same time ofday. The SRC may decide to require fed or fasted dosing of AZD9833(i.e., no food for a minimum of 2 hours prior to and 1 hour after eachAZD9833 dose), depending on emerging study data. Alternative dosingfrequencies or intermittent schedules of AZD9833 may be initiatedfollowing recommendation by the SRC in response to emerging safety,tolerability, and PK data.

Dosing will begin at 75 mg once daily. At each dose level, 1 subjectwill be exposed and monitored until Day 8; for details. After each doselevel during the dose escalation phase of the study, the SRC willevaluate all available safety information. The dose for subsequentcohorts or a decision to stop recruitment will be agreed by the SRCafter review of the data from each cohort. Dose escalation andde-escalation will be decided by the SRC. The proposed dose escalationscheme will allow for a doubling in dose with each cohort in principle,e.g. 75 mg, 150 mg, 300 mg, etc. However, alternative or intermediatedose levels may be tested following review of safety data by the SRC.

At least 2 subjects in each dose level in Part A and at least 5 subjectsin each cohort in Part B will be selected such that they are suitablefor and consent to provide one pre-treatment and one on-treatment pairedtumour biopsy sample. In the event that a subject has been selected forprovision of paired biopsies, and this becomes clinically unfeasibleduring the course of their care, the individual cohorts may be expandedby recruiting additional biopsy-eligible subjects until the requirednumber of evaluable biopsy pairs in each cohort have been collected.

There is no maximum duration of treatment, and subjects may continue toreceive AZD9833 as long as they are continuing to show clinical benefit,as judged by the investigator. If AZD9833 is discontinued for reasonsother than disease progression, the subject must continue tumourassessments until disease progression, or until a further line ofanti-cancer therapy is administered.

Dose Limiting Toxicity (DLT):

a DLT is defined as an AE or abnormal laboratory value that occurs fromthe first dose of AZD9833 up to and including Day 28, Cycle 1 (the DLTperiod) that is assessed as unrelated to disease progression,intercurrent illness, or concomitant medications and that, despiteoptimal therapeutic intervention, meets any of the following criteria:

-   -   (a) Any death not clearly due to the underlying disease or        extraneous causes    -   (b) Haematological toxicities as follows (CTCAE):        -   (i) Any ≥Grade 4 haematological toxicity present for more            than 4 consecutive days, or requiring blood transfusions,            G-CSF, or erythropoietins.        -   (ii) ≥Grade 3 neutropenia of any duration accompanied with            fever ≥38.5° C. and/or systemic infection.        -   (iii) ≥Grade 3 thrombocytopenia of any duration with            bleeding.        -   (iv) Grade 4 thrombocytopenia (regardless of duration or            bleeding)    -   (c) Any non-haematological toxicity CTCAE≥Grade 3 but with the        following conditional stipulations:        -   (i) Nausea ≥CTCAE Grade 3 for more than 3 consecutive days            despite administration of maximal anti-emetic therapy.        -   (ii) Vomiting ≥CTCAE Grade 3 for more than 3 consecutive            days despite administration of maximal anti-emetic therapy.        -   (iii) Vomiting ≥CTCAE Grade 4 (regardless of duration)        -   (iv) Diarrhea ≥CTCAE Grade 3 for more than 3 consecutive            days despite administration of maximal anti-diarrheal            therapy.        -   (v) Diarrhea ≥CTCAE Grade 4 (regardless of duration)        -   (vi) CTCAE Grade ≥3 fatigue that persists for more than 4            days.        -   (vii) CTCAE Grade ≥3 increase in creatinine.    -   (d) Other toxicity:        -   (i) QTcF value >500 ms or QTcF prolongation from baseline by            60 ms and >480 ms confirmed on at least 2 separate ECGs.        -   (ii) ≥CTCAE Grade 4 electrocardiogram QT corrected interval            prolongation.        -   (iii) An increase in serum/plasma AST or ALT≥3×ULN and            concurrent TBL≥2 ULN.    -   (e) Any other toxicity that:        -   (i) Is greater than at baseline and is clinically            significant and/or unacceptable despite optimal therapeutic            intervention, and is judged to be a DLT by the SRC, or        -   (ii) Results in a disruption of the dosing schedule of more            than 14 days despite optimal therapeutic intervention.

Background Medication:

Pre-menopausal women must have commenced treatment with an LHRH agonistat least 4 weeks prior to starting AZD9833 and continue LHRH agonisttherapy throughout the duration of the study.

Efficacy Assessment:

Anti-tumour activity will be evaluated using RECIST 1.1 by investigatorassessments. Baseline tumour assessments should encompass all areas ofknown predilection for metastases in the disease under evaluation andshould additionally investigate areas that may be involved based onsigns and symptoms of individual subjects. Baseline assessments shouldbe performed no more than 28 days before the start of AZD9833, ideally,as close as possible to the start of AZD9833. The methods of assessmentused at baseline should be used at each subsequent assessment duringtreatment and follow-up part of the study. Any other sites at which newdisease is suspected should also be appropriately imaged.

If an unscheduled assessment is performed and the subject has notprogressed, every attempt should be made to perform subsequentassessments at the scheduled visits while the subject remains on AZD9833or until she has progressed. Categorisation of objective tumour responseassessment will be based on the RECIST 1.1 guidelines for response:complete response (CR), partial response (PR), stable disease (SD), andprogression of disease (PD). For subjects who only have non-measurabledisease at baseline, categorisation of objective tumour responseassessment will be based on the RECIST 1.1 guidelines for response fornon-target lesions (NTLs): CR, PD, and non-CR/non PD. If theinvestigator is unsure whether progression has occurred, particularlywith response to NTLs or the appearance of a new lesion, it is advisableto continue AZD9833 and reassess the subject's status at the nextscheduled assessment, or sooner if clinically indicated. To achieve‘unequivocal progression’ on the basis of non-target disease, there mustbe an overall level of substantial worsening in non-target disease suchthat, even in presence of SD or PR in the target disease, the overalltumour burden has increased sufficiently to merit discontinuation oftherapy. A modest increase in the size of one or more NTLs is usuallynot sufficient to qualify for unequivocal disease progression status.

Safety and Clinical Assessments:

The safety and tolerability of AZD9833 is the primary objective of thisstudy. Related outcome measures are DLTs, AEs/SAEs, vital signs,clinical chemistry/haematology, and ECGs.

Clinical Safety Laboratory Assessments:

Clinical chemistry, haematology, and urinalysis and coagulation will beperformed at a local laboratory at or near to the investigator studysite. Sample tubes and sample sizes may vary depending on laboratorymethod used and routine practice at the study site.

Pharmacokinetics:

The characterisation of the pharmacokinetics of single and multipledoses of AZD9833 is a secondary objective of this study. Any residualsample remaining after PK analysis has been performed may be used toidentify, characterise, and establish the concentration of AZD9833metabolites and drug-related products in plasma, and/or to conductexploratory biomarker research. Analysis of AZD9833 in plasma and urinewill be performed using appropriate bioanalytical methods. Full detailsof the analytical methods used will be described in separatebioanalytical reports.

All samples within the known stability of the analytes of interest atthe time of receipt by the bioanalytical laboratory will be analysed. Inaddition, the PK samples may be subjected to further analyses toidentify, characterise, and establish the concentration of metabolitesin plasma. Any results from such analyses will be reported separatelyfrom the clinical study report. Incurred sample reproducibilityanalysis, if any, will be performed with the bioanalysis of the testsamples. The results from the evaluation will not be reported in theclinical study report but, separately, in a bioanalytical report.

Pharmacodynamics:

Pharmacodynamic measurements will be made on a number of biomarkers (e.g., optional tumour biopsies, plasma ctDNA, CTC, and archival tumourtissue). Biological samples (archival tumour tissue, mandatory andoptional biopsies where applicable) will be collected for the analysisof tumour DNA as an exploratory objective in this study. A 2-mL bloodsample for DNA isolation will be collected prior to administration ofthe first dose of AZD9833 from subjects who have consented toparticipate in the genetic analysis component of this study. If for anyreason the sample is not drawn prior to dosing, it may be taken at anyvisit until the last study visit. Only one sample for genetic researchshould be collected per subject during the study. Participation isoptional. Subjects who do not wish to participate in the geneticresearch may still participate in the study.

Biomarkers:

The following samples for exploratory biomarker research are optional orrequired, as indicated, and will be collected from the appropriatesubjects.

In Part A, paired tumour biopsy samples will be taken from at least 2subjects at each dose level. In Part B, these biopsies will be takenfrom at least 5 post-menopausal subjects at each AZD9833 dose level, 300mg, 150 mg and 75 mg and at least 5 from pre-menopausal subjects at 300mg. If subjects are willing to participate in this part of the study,they will sign a biopsy-specific written informed consent. Paired tumourbiopsies will be obtained from subjects with accessible tumours who haveconsented to biopsies. Accessible lesions are defined as tumour lesionsthat are biopsiable, and amenable to repeat biopsy.

The pre-treatment biopsy will be taken during screening as close aspossible to starting treatment. The on-treatment sample should be takenon Day 1 (±7 days) of Cycle 2 but can be taken outside this time window,if agreed with AstraZeneca. A further (optional) tumour biopsy shouldalso be taken on disease progression or at the end of treatment. Thebiomarkers to be investigated using tumour samples may include, but willnot necessarily be limited to: ER, PgR, Ki67, genomic/geneticalterations, and other ER-regulated gene expression. Where feasible,collection of a tumour biopsy at disease progression is encouraged. Thissample will be used to investigate changes in pathway signalling andpotential mechanisms of resistance (i. e., genetic alterations orevidence of alternative pathway activation).

Formalin-fixed archival tumour tissue embedded in paraffin blocks are tobe retrieved for all subjects, where available. If baseline biopsysamples can also be collected, retrieval of the archival diagnostictumour material is still required to provide data on how the tumour hasevolved since diagnosis. The archival samples can be derived from theprimary tumour and/or metastatic site and, where possible, the mostrecently acquired archival sample is required. Freshly preparedunstained slides from the archival tumour block are accepted, if tumourblocks cannot be submitted. From submitted archival tumour blocks, coresmay be removed to construct tissue microarrays for later biomarkeranalysis. The remaining part of the tumour block may be returned to theinstitution.

One 2-mL blood sample will be taken at each of the timepoints, forcancer antigen CA15-assessment.

Blood samples will be taken at each of the timepoints. These sampleswill be taken to obtain a preliminary assessment of AZD9833 activity inthe tumour by evaluation of pharmacodynamic biomarker changes, which mayinclude but are not limited to total counts, and expression levels ofER, Ki67 protein, and ER-regulated genes.

One 10-mL blood sample will be taken at the timepoints below to provide2 samples of plasma and one sample of serum per timepoint. The sampleswill be collected and stored to permit retrospective exploratorybiomarker analysis and will be analysed for a range of oncologybiomarkers that may correlate with drug response.

Two 2.5-mL whole blood samples will be collected in PAXgene tubes forRNA and microRNA/RNA samples preparation. Analysis of RNA may beconducted to generate hypotheses associated with the mechanisms ofaction of the molecule evaluated in the study and to potentiallyidentify changes in gene expression that correlate with treatmentresponse.

One 20-mL blood sample will be taken at screening, and 10-mL bloodsample will be taken at all of the other timepoints to provide plasma.It will be used for the extraction and analysis of ctDNA for theanalysis of predictive and pharmacodynamic biomarkers to interrogatechanges in genetic alterations and potential mechanisms of resistance.

Clinical Trial Results

A clinical trial according to the above protocol was carried out using60 patients. The results can be summarised as follows.

60 patients were treated (median age 61 (range 39-79)) across fivedoses; 25 mg QD n=12, 75 mg QD n=12, 150 mg QD n=13, 300 mg QD n=13, 50mg QD n=10. AZD9833 exposure was dose proportional after multiple doses,with a median terminal t1/2 of 12 h.

Treatment-related AEs experienced by 210% of patients were visualdisturbances (53%; 91% G1, 6% G2, 3% G3), bradycardia/sinus bradycardia(45%; 93% G1, 7% G2), nausea (18%; 46% G1, 55% G2), fatigue (13%; 38%G1, 63% G2), dizziness (10%; 83% G1, 17% G3) vomiting (10%; 50% G1, 33%G2, 17% G3), and asthenia (10%; 67% G1, 33% G2). Three patientsexperienced DLTs: G3 QTcF prolongation (300 mg); G3 vomiting (450 mg);and a combination of G2 visual disturbance, G2 headache and G2 gaitdisturbance (450 mg). DLT cases were managed with dose reduction. No G4or 5 AEs were reported. None of the observed AEs were deemed to beclinically relevant.

Efficacy data are presented in the table below; objective response rate(ORR) and clinical benefit rate (CBR) at 24 weeks:

TABLE 5 25 mg 75 mg 150 mg 300 mg 450 mg Total (n = 12) (n = 12) (n =13) (n = 13) (n = 10) (n = 60) ORR (%) 1/9 (11.1) 1/7 (14.3) 2/11 (18.2)2/10 (20.0) 1/6 (16.7) 7/43 (16.3) CBR (%) 4/12 (33.3) 8/12 (66.7) 4/13(30.8) 3/11 (27.3) 3/4 (75.0) 22/52 (42.3)

ER signalling pathway modulation was observed in all dose cohorts. Inpatients where clinical responses occurred and paired biopsies obtained,98% reduction in Ki67 was measured.

These data show that AZD9833 has an encouraging efficacy anddose-dependent safety profile. Evidence of clinical benefit and targetengagement was observed at all dose levels in women with ER+ ABC,including patients pre-treated with CDK4/6 inhibitors and fulvestrant,and those with ESR1 mutations.

1.-28. (canceled)
 29. A method of treating cancer in a human or animalpatient in need of such treatment, comprising administering to thepatient a compound, or a pharmaceutically acceptable salt thereof, oncedaily at a dose between 25 mg and 450 mg, wherein the compound isN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine.30. The method of claim 29, wherein the dose is selected from 25 mg, 75mg, 150 mg, 300 mg, and 450 mg.
 31. The method of claim 29, wherein thecompound is administered as a single dose unit or as multiple doseunits.
 32. The method of claim 31, wherein the compound is administeredas a single tablet.
 33. The method of claim 29, wherein the compound isadministered in combination with a further anti-cancer therapy.
 34. Themethod of claim 29, wherein the compound is administered in combinationwith a CDK inhibitor.
 35. The method of claim 34, wherein the compoundis administered in combination with palbociclib, ribociclib,abemaciclib, lerociclib, or trilaciclib.
 36. The method of claim 34,wherein the compound is administered in combination with palbociclib.37. The method of claim 29, wherein the compound is administered incombination with an mTOR inhibitor.
 38. The method of claim 37, whereinthe compound is administered in combination with everolimus.
 39. Themethod of claim 29, wherein the cancer is selected from breast cancerand gynaecological cancer.
 40. The method of claim 39, wherein thecancer is ER-positive HER2-negative advanced breast cancer.
 41. Themethod of claim 29, wherein the compound is administered to a pre- orpost-menopausal woman.
 42. The method of claim 29, wherein the cancerhas previously been treated with one or more endocrine therapies and nomore than two prior chemotherapies for ER-positive HER2-negativeadvanced breast cancer.
 43. The method of claim 29, wherein the compoundis administered to a patient whose cancer is resistant to non-steroidalaromatase inhibitors.
 44. The method of claim 29, wherein the doseachieves a mean peak blood plasma concentration in the patient between10 ng/mL and 1000 ng/mL.
 45. The method of claim 29, wherein the dose ofthe compound achieves a median terminal half-life in the patient between8 hours and 14 hours.
 46. The method of claim 29, wherein the doseachieves a median terminal half-life in the patient of 12 hours.
 47. Themethod of claim 29, wherein the dose achieves an objective response ratein the patient between 10% and 20%.
 48. The method of claim 29, whereinthe dose does not cause any serious side-effects in the patient.
 49. Anoral pharmaceutical composition comprising between 25 mg and 450 mg of acompound, or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable excipient; wherein the compound isN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine.50. The composition of claim 49, wherein the composition contains 25 mg,75 mg, 150 mg, 300 mg, or 450 mg of the compound.
 51. The composition ofclaim 50, wherein the composition contains 75 mg of the compound. 52.The composition of claim 50, wherein the composition contains 150 mg ofthe compound.
 53. The composition of claim 49 in the form of a singletablet.
 54. A kit comprising: an oral pharmaceutical compositioncomprising from 25 mg to 450 mg ofN-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine,or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient; and instructions for the use ofthe composition in the treatment of cancer.
 55. The kit of claim 54,further comprising an additional anti-cancer agent for administration incombination with the composition.